Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with a 5 year survival that has remained at 50% for the last 30 years. Immunotherapeutic approaches for OSCC patients may be alternative treatments. Unfortunately, OSCC patients have profound immune defects mediated by tumor-induced immune suppressor cells including tumor-mobilized CD34+ progenitor cells and Treg. Our past in vitro studies and our ongoing VA merit-review trial are showing that 11,25-dihydroxyvitamin D3 [1,25(OH)2D3] induces differentiation of immune suppressive CD34+ progenitor cells into immune stimulatory dendritic cells. However, we recently also showed that OSCC induce endothelial cells to become immune inhibitory by stimulating them to produce the immune suppressive mediator PGE2 which, in turn, induces their production of the suppressive mediator IL-6. Both PGE2 and IL-6 stimulate other suppressive cell types such as M2 macrophages and Treg cells. The hypothesis of this study is beneficial T-cell reactivity in OSCC tumors can be synergistically stimulated by blocking suppressor endothelial cells and their induction of other inhibitory cell populations while also maturing immune inhibitory CD34+ cells into antigen-presenting dendritic cells. To test this hypothesis, newly diagnosed OSCC patients will be administered the COX-2 inhibitor celecoxib and/or 1,25(OH)2D3 for the 3 week duration between cancer diagnosis and surgical treatment. The following aims will test the immunological and clinical effectiveness of the combination treatment: #1 To block the suppressive activity of endothelial cells and increase the levels of dendritic that are stimulatory to T-cell reactivity, thereby synergistically increasing intratumoral T-cell reactivity. These functional immune analyses will use OSCC tissues removed from untreated patients or patients treated with celecoxib and/or 1,25(OH)2D3. #2: To reduce development of OSCC recurrences by synergistically stimulating intratumoral T-cell reactivity with celecoxib to block suppressor endothelial cell activity and 1,25(OH)2D3 to mature CD34+ suppressor cells into T-cell stimulatory dendritic cells. The long-term application of these studies is to use treatments that block immune suppressor cells and enhance dendritic cell maturation together with T-cell activation vaccines targeting OSCC. The results of these studies will be applicable to other types of malignancies that induce immune suppressive cells, including lung and prostate cancer, which are increasing in prominence in the aging Veterans population. PUBLIC HEALTH RELEVANCE: The 2 year cancer recurrence rate for Veterans with oral cancer (OSCC) is 50%. Oral cancer has received considerable attention in the VA due to its strong link with smoking plus alcohol consumption, and the high incidence of these risk factors among the military and Veteran populations. Furthermore, a report entitled "Gulf War and Health, Vol. 3: Fuels, Combustion Products and Propellants" issued by the VA in December 2004 raised concerns about possible increased incidence of cancer due to exposures during the Gulf War. The poor survival of veterans with OSCC underscores the significance of identifying new treatment approaches. The proposed studies will test a new 2-pronged immunotherapeutic approach for OSCC patients that lessens the immune inhibitory environment while maturing cells that can stimulate T-cell reactivity to OSCC. The results of the proposed immunotherapeutic studies will be applicable to other types of malignancies such as lung and prostate cancer, which are increasing in prominence in the aging Veterans population.